The novel intermediate compound crystalline 7-[2-(2-fomylaminothiazol-4-yl)-2 -(Z)-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid-1 -(isopropoxy/crystallization of cefpodoxime proxetil. The crystallization process comprises dissolving or suspending the intermediate in the presence of a nitrile or a ketone or mixtures thereof; at a ratio of 1 gm of the intermediate to 2-15 ml nitrile; or at a ratio of 1 gm of the intermediate to 3-15 ml ketone; in the presence of 5-80 ml water; and thereafter isolating the intermediate in crystalline form and converting the intermediate by splitting off the formyl group from the amino group attached to the thiazolyl group, to obtain the desired product cefpodoxime proxetil, in the form of a diastereoisomeric mixture in a ratio of b/(A+b) of 0.5 to 0.6.
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as a diastereoisomeric mixture in crystalline form having a diastereoisomeric ratio b/(A+b) is 0.4 to 0.7, wherein b is the more apolar of the two diastereoisomers, wherein the chiral center is marked with a (*).
said process comprising:
(a) dissolving a compound of formula I in a solvent selected from the group consisting of a nitrile, a ketone, and mixtures thereof, to form a solution, wherein the amount of nitrile is 2-15 ml, based on 1 gm of the compound of formula I, and the amount of ketone is 3-15 ml, based on 1 gm of the compound of formula I;
(b) treating the solution with water to induce precipitation of the compound of formula I in crystalline form, wherein the amount of water in the case of a nitrile solvent is 5-80 ml, based on 1 gm of the compound of formula I, and the amount of water in the case of a ketone solvent is 10-40 ml, based on 1 gm of the compound of formula I; and
(c) isolating the compound of formula I in crystalline form.
1. A process for preparing a mixture of diastereoisomers of cefpodoxime proxetil of formula ii
##STR00005##
in a diastereoisomeric ratio b/(A+b) of 0.4 to 0.7. wherein b is the more apolar of the two diastereoisomers, wherein the chiral center is marked with a (*), said process comprising (i) acylating a compound of formula iii
##STR00006##
with Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid, to form a mixture of diastereoisomers of a compound of formula I
##STR00007##
(iii) dissolving the mixture of diastereoisomers of a compound of formula I in a solvent selected from the group consisting of a nitrile, a ketone, and mixtures thereof, to form a solution, wherein the amount of nitrile is 2-15 ml, based on 1 gm of the compound of formula I, and the amount of ketone is 3-15 ml, based on 1 gm of the compound of formula I;
(iv) treating the solution with water to induce precipitation of the compound of formula I in crystalline form, wherein the amount of water in the case of a nitrile solvent is 5-80 ml, based on 1 gm of the compound of formula I, and the amount of water in the case of a ketone solvent is 10-40 ml, based on 1 gm of the compound of formula I;
(v) isolating the compound of formula I in crystalline form; and
(vi) hydrolyzing the compound of formula I in crystalline form to form a diastereoisomeric mixture in a ratio of b/(A+b) of 0.4 to 0.7 of a compound of formula ii.
2. The process according to
3. The process according to
5. The process according to
10. The compound according to
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This is a continuation of International Application No. PCT/EP 00/03941, filed May 3, 2000.
The present invention relates to β-lactams, particularly to cefpodoxime proxetil, of formula
##STR00001##
e.g. described in The Merck Index, Twelfth Edition, Item 1991; more particularly to a process for the adjustment, e.g. change, of the diastereoisomeric ratio of the two existing diastereoisomers being with respect to the carbon atom attached to the oxygen of the ester group in the carboxyl ester group in position 4 of the ring system (marked with a star (*) in formula II). A diastereoisomeric ratio B/(A+B) of cefpodoxime proxetil currently on the market may be around 0.53. B is the more apolar of the two diastereoisomers. Because of different bioavailability of these individual diastereoisomers a commercial form for oral administration of cefpodoxime proxetil has to be within a defined ratio B/(A+B). A diastereoisomeric ratio B/(A+B) of 0.5 to 0.6 has been found to be bioequivalent with a commercial form. Determination of the diasterisomeric content of the diastereoisomers A and B in cefpodoxime proxetil may be carried out by HPLC, e.g. according to a method as described in Pharmacopeial Forum, Vol. 23, No. 4, p. 4388 ff (1997), the content of which is incorporated herein by reference, e.g. from which a diastereoisomeric ratio B/(A+B) and A/(A+B) may be calculated.
One process in the production of cefpodoxime proxetil may be carried out via acylation of 7-amino-3-methoxy-methyl-3-cephem-4-carboxylic acid-1-(isopropoxycarbonyloxy)ethyl-ester of formula
##STR00002##
with activated Z-2-(methoxyimino)-2-(2-formylaminothiazol-4-yl)-acetic acid to obtain 7-[2-(2-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester (N-formyl cefpodoxime proxetil) of formula
##STR00003##
It was found that a mixture of diastereoisomers of a compound of formula I may be obtained in a diastereoisomeric ratio B/(A+B) of 0.40 to below 0.50. The reaction for splitting off the formyl group in a compound of formula I obtained to obtain cefpodoxime proxetil may have no significant influence on the diastereoisomeric ratio B/(A+B) and consequently B/(A+B) in cefpodoxime proxetil obtained from a process as described above may be outside of 0.5 to 0.6.
Surprisingly a simple process has now be found wherein cefpodoxime proxetil may be obtained in high purity; e.g. in a diastereoisomeric ratio which is 0.4 to 0.7, e.g. 0.5 to 0.6.
A compound of formula I may be produced, e.g. in conventional manner and e.g. as follows:
The carboxylic acid group in position 4 of the ring system of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (AMCA), e.g. of formula
##STR00004##
which is a known compound and obtainable, e.g. according to a method as conventional, may be esterified to obtain a compound of formula III. This may be effected according to a method as conventional, e.g. by reacting AMCA with a compound of formula
X—CH—(CH3)—O—CO—O—CH(CH3)2 V
wherein X denotes a leaving group, e.g. a conventional leaving group, such as a halogenide, e.g. an iodide; e.g. in the presence of a solvent (system). Esterification may be effected e.g. in conventional solvent (system), e.g. organic solvent, such as ketones, e.g. acetone; nitriles, e.g. acetonitrile; acetamides, e.g. dimethylacetamide; and halogenated hydrocarbons, e.g. dichloromethane; and e.g. in the presence of a base; e.g. an amidine, such as 1,5-diazabicyclo(4,3,0)non-5-ene (DBN) or 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU); or a guanidine, e.g. a linear guanidine, such as tetramethylguanidine, pentamethylguanidine, tetraethylguanidine, tetramethylethylguanidine and tetramethylbenzylguanidine or a cyclic or bicyclic guanidine, e.g. 1,5,7-triazabicyclo-(4,4,0)-dec-5-ene, and 7-methyl, 7-ethyl, 7-benzyl and 7-phenyl derivatives thereof. A compound of formula III obtained may be isolated, if desired, e.g. according to a method as conventional.
The amine group in position 7 of the ring structure of a compound of formula III, e.g. obtained as described above, e.g. with or without isolation from a corresponding reaction mixture, preferably without isolation, may be acylated e.g. according to a method as conventional. This may be effected e.g. by reaction of a compound of formula III obtained in the esterification reaction, with activated Z-(2-formylaminothiazol-4-yl)-methoxyimino acetic acid, e.g. including an ester or an acid halogenide, such as Z-(2-formylaminothiazol-4-yl)-methoxyimino-acetic acid chloride, e.g. in the form of a salt, e.g. a hydrochloride, including activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid obtainable by a Vilsmeier reaction. Vilsmeier activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid may be produced e.g. in conventional manner, e.g. in situ in the reaction mixture e.g. by treating Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid with phosphoroxyhalogenide, e.g. chloride, e.g. under Vilsmeier reaction conditions.
Acylation may be carried out in organic solvent (system), including e.g. carboxylic acid esters, e.g. acetates, such as ethyl acetate; halogenated hydrocarbons, e.g. aliphatic, such as dichloromethane, e.g. in dichloromethane; in the presence of a nitrite or a ketone; e.g. in the presence of an amide, e.g. N,N-dimethylformamide (DMF); e.g. in the presence of pH adjustment. pH Adjustment may be effected e.g. by addition of a base, such as an inorganic base, e.g. a carbonate or bicarbonate, e.g. sodium and potassium, or e.g. of an, e.g. weakly, basic anionic exchange resin, to obtain a pH of ca. 2.5 to 8.0. Surprisingly pH adjustment may alternatively also be avoided. A compound of formula I may be obtained in the reaction mixture. According to the present invention a compound of formula I may be obtained in crystalline form.
A compound of formula I in crystalline form may be produced as follows:
N-formyl cefpodoxime proxetil may be suspended or dissolved in a nitrite, or in a ketone; e.g. including mixtures thereof; and may crystallise, e.g. and water may be added to the mixture.
A nitrile, e.g. a (C2-5)nitrile, includes for example acetonitrile, propionitrile or butyronitrile, preferably acetonitrile. A ketone, e.g. a (C2-4)ketone, includes for example acetone or methyl ethyl ketone, preferably acetone.
The temperature during crystallisation is not critical. A compound of formula I may crystallise at, below, or higher than room temperature, e.g. at room temperature; in an ice-bath, or up to 70° C. Temperatures of 20 to 40° C. are preferred.
Crystallisation of a compound of formula I from organic solvent comprising a nitrite or a ketone may result in a mixture of diastereoisomers of a compound of formula I in a diastereoisomeric ratio B/(A+B) of 0.4 to 0.7.
We have found surprisingly that water may have an influence in respect with a desired diastereoisomeric ratio of N-formyl cefpodoxime diastereoisomers and that a diastereoisomeric ratio of 0.5 to 0.6 may be adjusted by addition of appropriate amounts of water to a mixture containing a compound of formula I and a nitrile or a ketone.
Alternatively, N-formyl cefpodoxime proxetil may be suspended or dissolved, preferably dissolved, in organic amide or urea, preferably in organic amide, for example DMF, or in organic amide in combination with a ketone, for example acetone; a nitrile, for example acetonitrile; an ester, for example ethyl acetate; or a halogenated hydrocarbon, for example dichloromethane, e.g. dichloromethane in combination with a nitrile or a ketone. If not already present a nitrile or a ketone, e.g. and water, is added to the mixture obtained. A compound of formula I may crystallise and may be obtained in crystalline form, e.g. a mixture of diastereoisomers of a compound of formula I in a diastereoisomeric ratio B/((A+B) of 0.4 to 0.7, such as 0.5 to 0.6 may be obtained.
The ratio of water/organic solvent is critical, not only for crystallisation, but for a desired diastereoisomeric ratio and for a high purification effect of a compound of formula I. Higher amount of organic solvent may result in a higher diastereoisomeric ratio B/(A+B). E.g. from pure acetonitrile as a solvent a compound of formula I may be obtained in a diastereoisomeric ratio B/(A+B) of 0.63.
If too much water is present, the purification effect in the crystallisation step may be insufficient. An appropriate amount of water may easily be found out, e.g. by determining purity and the diastereoisomeric ratio B/(A+B) for different amounts of water present. Preferred solvent ratios include e.g. 2 to 15 ml, preferably 3 to 10 ml of a nitrile, preferably acetonitrile, and 5 to 80 ml, preferably 10 to 50 ml of water, based on 1 g of a compound of formula I. The solvent ratio may also depend whether and in which amount an organic amide e.g. DMF is present. E.g. DMF may be present in the solvent system, e.g. 1 to 20 ml, preferably 2 to 15 ml; DMF per g of a compound of formula I.
If a compound of formula I is crystallised from a ketone, e.g. acetone and water, preferred amounts of acetone and water include 3 to 15 ml, preferably 3 to 10 ml of a ketone, e.g. acetone; and 10 to 40 ml, preferably 15 to 30 ml of water; per g of a compound of formula I.
N-formyl cefpodoxime proxetil may also be produced directly from a reaction mixture wherein N-formyl cefpodoxime is obtained, e.g. as follows:
To a mixture containing a compound of formula I, e.g. obtained in a corresponding reaction an organic amide, e.g. DMF or urea is added, e.g. if not already present; and solvent is removed, e.g. by distillation, evaporation. The residue obtained is mixed with a nitrile or a ketone; e.g. and water. Alternatively, if acylation is carried out in dichloromethane, a nitrile or a ketone may be added after removal of the solvent; e.g. and water may be added to the residual mixture obtained. N-Formyl cefpodoxime proxetil may crystallise and may be isolated from the reaction mixture, e.g. according to a method as conventional. Crystalline N-formyl cefpodoxime proxetil in crystalline form is new.
In one aspect the present invention provides a compound of formula I in crystalline form.
Production of a compound of formula I in crystalline form may have a high purification effect, e.g. in (part of) a production sequence from AMCA to N-formyl cefpodoxime.
We have surprisingly additionally found, that N-formyl cefpodoxime produced according to the present invention may crystallise in a diastereoisomeric ratio B/(A+B) of 0.5 to 0.6.
In another aspect the present invention provides a process for the production of a compound of formula I in crystalline form, e.g. a mixture of diastereoisomers of a compound of formula I, comprising crystallizing a compound of formula I in organic solvent comprising a nitrile, e.g. a (C2-4)nitrile; or a ketone, e.g. a (C3-5)ketone; e.g. in the presence of water, e.g. wherein the diastereoisomeric ratio B/(A+B), wherein B is the more apolar of the two diastereoisomers, is 0.5 to 0.6, the diastereoisomers being with respect with the carbon atom marked with a star in formula I.
In still another aspect the present invention provides the use of crystalline N-formyl cefpodoxime proxetil in the purification of cefpodoxime proxetil, e.g. in the form of a mixture of diastereoisomers of a compound of formula I, wherein the diastereoisomeric ratio B/(A+B), wherein B is the more apolar of the two diastereoisomers, is 0.5 to 0.6, the diastereoisomers being with respect with the carbon atom marked with a star in formula I.
In another aspect the present invention provides a process for the adjustment, e.g. change, of the diastereoisomeric ratio B/(A+B) wherein B is the more apolar of the two diastereoisomers; of a mixture of diastereoisomers of cefpodoxime proxetil, e.g. adjusting a diastereoisomeric ratio B/(A+B) to 0.5 to 0.6; the diastereoisomers being with respect with the carbon atom marked with a star in formula I, comprising crystallizing a compound of formula I from a mixture comprising water and either a nitrile, e.g. a (C2-5)nitrile, or a ketone, e.g. a (C3-5)ketone; e.g. including mixtures thereof; and converting the crystalline compound of formula I obtained into cefpodoxime proxetil.
In a further aspect the present invention provides a process for the purification of cefpodoxime proxetil, comprising producing a compound of formula I as defined in claim 1 and crystallizing in the presence of a nitrile or a ketone and converting a crystalline compound of formula I into cefpodoxime proxetil.
In still another aspect the present invention provides a process for the production of a mixture of diastereoisomers of cefpodoxime proxetil of formula II in a diastereoisomeric ratio B/(A+B), wherein B is the more apolar of the two diastereoisomers, of 0.5 to 0.6, the diastereisomers being with respect with the carbon atom marked with a star in formula II, comprising producing a mixture of diastereoisomers of a compound of formula I by acylating a compound of formula III with activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid, removing solvent from the reaction mixture obtained, crystallizing a compound of formula I in the residue obtained in the presence of a nitrile or a ketone, e.g. in the presence of water; isolating a compound of formula I in crystalline form and converting a compound of formula I by splitting off the formyl group from the amino group attached to the thiazolyl group, to obtain a compound of formula I, in the form of a diastereoisomeric mixture in a ratio of B/(A+B) of 0.5 to 0.6, e.g. wherein a compound of formula III is produced by esterifying 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid with a compound of formula V wherein X denotes a leaving group.
Advantages of a process according to the present invention includes e.g.:
In still another aspect the present invention provides a crystalline 7-[2-(2-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid-1-(isopropoxycarbonyloxy)ethyl ester of formula I as a diastereoisomeric mixture of formula I (*signifies the asymmetric centre) and a process for the production of the diastereoisomeric mixture of formula I, whereby a compound of formula III is acylated with a reactive derivative of (2-N-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetic acid and the compound of formula I is crystallised in water and a (C1-4)nitrile or water and a (C3-5)ketone, e.g. whereby the compound of formula III is produced by the esterification of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid of formula IV with a compound of formula V wherein X signifies a leaving group, in the presence of a base.
In the following examples all temperatures are given in degrees celsius.
The following abbreviations are used:
3 g of amorphous N-formyl cefpodoxime proxetil with a diastereoisomeric ratio B/(A+B) of 0.51 and a HPLC purity of 97% are dissolved in a mixture of 6 ml of DMF and 18 ml of acetone. The solution is heated to 40° and 20 ml of water are added while stirring and after seeding further ca. 40 ml of water are added dropwise while stirring. Crystallisation occurs and the crystalline precipitate is filtrated off and dried. N-Formyl cefpodoxime proxetil in crystalline form is obtained comprising a mixture of diastereoisomers with a diastereoisomeric ratio of B/(A+B)=0.58.
Seed crystalls are obtained in preliminary crystallisation tests.
a) Is carried out as example 1, with the following differences:
b) Is carried out as example 2a), with the following differences:
a) Preparation of AMCA-Ester
b) Activation of (2-N-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetic acid
c) Preparation of N-Formyl Cefpodoxime Proxetil
a) AMCA-Ester
b) (2-N-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetic Acid Chloride in the Form of a hydrochloride
c) N-Formyl Cefpodoxime Proxetil
20 ml of methanol and 0.48 ml of conc. H2SO4 are mixed and 4.0 g of N-formyl cefpodoxime proxetil obtained according to example 3c) are added to the mixture obtained. A solution is obtained, is stirred at room temperature for ca. 85 minutes, and is added dropwise, whilst stirring to a solution of 2 g of KHCO3 in 200 ml of water. Cefpodoxime proxetil precipitates, is isolated, washed with water and dried. Cefpodoxime proxetil in the form of a diastereoisomeric mixture with a diastereoisomeric ratio of B/(A+B)=0.51 and of an HPLC purity of 97.4% is obtained.
Ludescher, Johannes, Wolf, Siegfried, Greil, Julia, Totschnig, Klaus
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